Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH:4]([CH2:10][CH:11]=[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[Cl:21])[CH3:13])[C:5](OCC)=[O:6])=O.Cl.[NH2:23][C:24]([NH2:26])=[NH:25].[H-].[Na+]>C(O)C>[NH2:26][C:24]1[N:25]=[C:5]([OH:6])[C:4]([CH2:10][CH:11]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[CH3:13])=[C:2]([CH3:1])[N:23]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(CC=C(C)c1cc(Cl)ccc1Cl)C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC(=CCc1c(C)nc(N)nc1O)c1cc(Cl)ccc1Cl
Reaction time: 18 h
Yield: 96.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 5.0 grams (0.015 mole) of ethyl 2-methylcarbonyl-5-(2,5-dichlorophenyl)-4-hexenoate in 70 mL of ethanol is stirred, and 3.1 grams (0.032 mole) of guanidine hydrochloride is added. To this is then added dropwise a mixture of 1.5 grams (0.038 mole) of sodium hydride (60% in mineral oil) in 30 mL of ethanol. Upon completion of addition, the reaction mixture is warmed to reflux where it is stirred for about 18 hours. After this time the reaction mixture is cooled and concentrated under reduced pressure to a residual oil. The oil is stirred with 40 mL of aqueous 10% acetic acid, and the acid wash is decanted from the oil. This is repeated with an additional 40 mL of aqueous 10% acetic acid, and then with two 30 mL portions of water. The oil is dissolved in hot ethanol and the solution is placed in a refrigerator. The resultant solid is collected by filtration, yielding 4.7 grams of 2-amino-4-hydroxy-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine, mp>250° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C1(CN)CCCCC1.[O:14]=[C:15]1[C:23]2([CH2:27][O:26][C:25]3[CH:28]=[C:29]4[C:33](=[CH:34][C:24]2=3)[CH2:32][CH2:31][O:30]4)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]1[CH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:40](=[O:41])[C:39]1[CH:43]=[CH:44][C:36]([CH2:35][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3([CH2:27][O:26][C:25]4[CH:28]=[C:29]5[C:33](=[CH:34][C:24]3=4)[CH2:32][CH2:31][O:30]5)[C:15]2=[O:14])=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: COCCN
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: COCCNC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-methoxyethylamine to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-methoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (49%) as a colorless solid: mp 182-183° C.; 1H NMR (300 MHz, CDCl3) δ7.81-7.73 (m, 2H), 7.44-7.37 (m, 2H), 7.23-7.15 (m, 2H), 7.07-7.00 (m, 1H), 6.77-6.70 (m, 1H), 6.56-6.41 (m, 3H), 5.00 (ABq, 2H), 4.85 (ABq, 2H), 4.60-4.51 (m, 2H), 3.68-3.60 (m, 2H), 3.59-3.52 (m, 2H), 3.38 (s, 3H), 3.08-2.94 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 166.9, 161.9, 161.3, 141.8, 139.3, 134.1, 132.6, 128.7, 127.6, 127.5, 124.0, 123.6, 120.0 (2C), 118.8, 109.1, 93.3, 80.6, 72.4, 71.1, 58.8, 57.7, 43.8, 39.7, 29.0; MS (ES+) m/z 471.1 (M+1).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=O.Cl.[NH2:12]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)#[N:12]
Reactant: NO
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)O)o1
Temperature: 85 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A 250-mL, three-neck, round-bottom flask equipped with a mechanical stirrer, a heating mantle, and a condenser was charged with 5-formyl-2-furancarboxylic acid (9.18 g, 65.6 mmol) and pyridine (60 mL). Hydroxylamine hydrochloride (5.01 g, 72.2 mmol) was added and the mixture was heated to 85° C. Acetic anhydride (40 mL) was added and the reaction was stirred at 85° C. for 3 h, after which time the solvent was evaporated at 40° C. under reduced pressure. The residue was dissolved in water, basified with 2.0 N NaOH solution to pH 9, and extracted with 4:1 dichloromethane/2-propanol until the pyridine was completely removed (5×200 mL). The aqueous solution was then acidified with 2.0 N HCl solution to pH 2, saturated with solid NaC1, and extracted with 4:1 dichloromethane/2-propanol (5×200 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to dryness. The residue was crystallized from dichloromethane to give 6.80 g of the title compound as a white solid (76%). Mass spectrum (ESI-neg, m/z) Calcd. for C6H3NO3, 136.0 (M−H). found 136.1. The 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:16])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].[Li+].[OH-].O>C1COCC1.CO.O>[CH3:16][N:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(-c2ccccc2)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccccc2)cc1C(=O)O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl-4-bromo-1-methyl-1H-pyrrole-2-carboxylate (2.5 g, 11.5 mmol) in DMF (35 mL) under argon were added sequentially Pd(PPh3)4 (0.66 g, 0.58 mmol) and phenyl boronic acid (3.46 g, 28.4 mmol). The reaction mixture was heated to 70° C., and Na2CO3 (11 g, 104 mmol) dissolved in water (30 mL) was added. The reaction mixture was heated to 110° C. (14 h), cooled to room temperature, diluted with water (250 mL), and extracted with diethyl ether (250 mL×3). The combined organic layers were dried and concentrated in vacuo. The residue was purified by silica chromatography (eluted with petroleum ether:ethyl acetate=40:1) to afford methyl-1-methyl-4-phenyl-1H-pyrrole-2-carboxylate as a white crystalline solid (0.257 g). The ester (0.26 g, 1.2 mmol) was then combined with LiOH/H2O (0.15 g, 3.6 mmol) in THF (5 mL), CH3OH (5 mL) and H2O (2.5 mL) and was stirred at 40° C. (4 h). Water (25 mL) was added and the mixture was washed with DCM (15 mL). The pH of the aqueous phase was adjusted to 5-7 using HCl (1N). The water was removed and the residue was dissolved in MeOH (100 mL) and then filtered. The filtrate was concentrated in vacuo to give 1-methyl-4-phenyl-1H-pyrrole-2-carboxylic acid as white solid. (0.419 g) 1H-NMR (CDCl3, 400 MHz): δ 4.01 (s, 3H), 7.16 (d, J=1.6 Hz, 1H), 7.23 (t, J=7.2 Hz, 1H), 7.38 (m, 3H), 7.53 (dd, J=7.2, 8.4 Hz, 2H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5](C=O)=[CH:4][N:3]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12].[C:36]1(C)C=CC=CC=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4](/[CH:36]=[CH:16]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:3][C:2]=1[Cl:1]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cnc(Cl)c(Cl)c1
Reactant: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(Cl)c(Cl)n1
Temperature: 25 °C
Yield: 16 %

Procedure:
A solution of crude 2,3-dichloro-5-formylpyridine and (carbethoxymethylene)triphenylphosphorane (2.14 g, 5.83 mmol) in toluene (12 mL) was heated at reflux overnight and then cooled to room temperature. After solvent removal at reduced pressure, the residue was chromatographed (9% to 10% EtOAc/hexane) to give 323 mg (16% from 5,6-dichloro-3-pyridinemethanol) of ethyl(E)-3-(5,6-dichloro-2-pyridinyl)-2-propenoate as a white solid, mp 102-103° C. IR 2914, 1702, 1428, 1193 cm−1; 1H NMR (CDCl3) δ 1.37 (t, J=7.2 Hz, 3H, OCH2CH3), 4.31 (q, J=7.2 Hz, 2H, OCH2CH3), 6.53 (d, J=16.2 Hz, 1H, CH═CHCO), 7.62 (d, J=16.2 Hz, 1H, CH═CHCO), 7.94 (d, J=1.8 Hz, 1H, 4-ArH), 8.44 ppm (d, J=1.8 Hz, 1H, 2-ArH). HRMS calcd C10H9Cl2NO2 [M+H]+ 246.0083. found 246.0086.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:20][O:21][C:22](=[O:30])[CH:23]=[C:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>CO>[CH3:20][O:21][C:22]([CH:23]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH2:11][Cl:10])[N:26]2[CH2:27][CH2:28][O:29][C:24]12[CH3:25])=[O:30]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COC(=O)C=C(C)NCCO
Solvent: CO
Product: CCOC(=O)C1=C(CCl)N2CCOC2(C)C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.6 %

Procedure:
A mixture of 2-chlorobenzaldehyde (XI, 57.0 g), ethyl 4-chloroacetoacetate (VIII, 69.3 g) and 3-(2-hydroxyethylamino)-but-2-enoic acid methyl ester (XXIII, 63.2 g) in methanol (800 mL) was stirred at room temperature for 48 h. Methanol was removed under reduced pressure and the residue dissolved in ethyl acetate (400 mL). The organic phase was washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (grade 9385, Merck, 230-400 mesh, 60 Å) using a solvent mixture of hexane and ethyl acetate as eluent (95:5, 90:10, 85:15, 80:20, 70:30 and 60:40) as eluent afforded the title compound (XXIV 30.0 g). 1H-NMR (CDCl3) δ (ppm): 0.80 (t, 3H, J=6.9 Hz), 1.05 (s, 3H), 3.73 (s, 3H), 3.39 (s, 1H), 3.74-4.09 (m, 4H), 4.06 (q, 2H, J=6.9 Hz), 4.51 (d, 1H, J=11.5 Hz),4.63 (s, 1H), 5.40 (d, 1H, J=11.5 Hz), 7.12-7.40 (m, 4H); 13C-NMR (CDCl3) δ (ppm): 13.6, 25.7, 39.3, 39.7, 45.8, 51.0, 51.7, 59.5, 63.4, 90.5, 98.6, 126.3, 126.8, 129.6, 129.9, 133.6, 140.7, 149.5, 167.5, 171.8; HRMS: calc. for C20H23Cl2 NO2 427.0953 found 427.0939; Elemental Analysis (%): calc. (found) C 56.09 (56.12), H 5.41 (5.26), N 3.27 (3.07); m.p. 141.9°-142.8° C.; IR(KBr, cm-1): 1742, 1676, 1581, 1566.
Reaction SMILES: [C:1]([C:3]([C:11]#[N:12])=[CH:4][C:5]([CH3:10])=COCC)#[N:2].[C:13](C(C#N)=CC(C)C(OCC)OCC)#N.[NH3:28]>>[NH2:28][C:11]1[C:3]([C:1]#[N:2])=[C:4]([CH3:13])[CH:5]=[CH:10][N:12]=1
Reactant: CCOC=C(C)C=C(C#N)C#N
Reactant: N
Reactant: CCOC(OCC)C(C)C=C(C#N)C#N
Product: Cc1ccnc(N)c1C#N

Procedure:
A solution of about 6.1 grams (0.038 mole) of a mixture of 1,1-dicyano-4-ethoxy-3-methyl-1,3-butadiene and 1,1-dicyano-4,4-diethoxy-3-methyl-1-butene in 200 mL of saturated methanolic ammonia is stirred at ambient temperature for about 15 hours. After this time the solvent is removed under reduced pressure, and the residue is partitioned between 160 mL of aqueous 1N hydrochloric acid and 160 mL of ethyl acetate. The aqueous layer is separated and poured into 160 mL of an aqueous solution saturated with sodium bicarbonate. The resultant solid is collected by filtration and dried, yielding about 2.6 grams of 2-amino-3-cyano-4-methylpyridine. Steps A and B are repeated.
Reaction SMILES: [CH3:1][C:2]1([C:7]2(/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.[H][H]>C1COCC1.[Pt](=O)=O>[CH3:1][C:2]1([C:7]2([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC(=O)/C=C/C1(C2(C)OCCO2)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CC(=O)CCC1(C2(C)OCCO2)CC1

Procedure:
1.23 g of 153 is dissolved in THF, and 200 mg of platinum(IV) oxide is added in an argon stream. Using a hydrogenating apparatus, it is hydrogenated until no more hydrogen is consumed, flushed with nitrogen, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.19 g of title compound 154 accumulates as a colorless oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:4]=1[C:5]([CH2:13][C:14]#N)=[CH:6][NH:7]2.[OH2:16].[CH3:17][OH:18]>>[CH3:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:4]=1[C:5]([CH2:13][C:14]([O:18][CH3:17])=[O:16])=[CH:6][NH:7]2
Reactant: O
Reactant: CO
Reactant: Cc1cc(C)c2c(CC#N)c[nH]c2c1
Agent: Cl
Product: COC(=O)Cc1c[nH]c2cc(C)cc(C)c12
Reaction time: 0.5 h

Procedure:
HCl (g) was bubbled through a solution of (4,6-dimethyl-1H-indol-3-yl)acetonitrile from Step B (83.0 mg, 0.450 mmol) in MeOH (5 mL). The reaction mixture was stirred for 30 min, then H2O (1 mL) was added and stirring was continued for 2 h. The MeOH was removed under vacuum and the reaction mixture was extracted with EtOAc (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was dissolved in MeOH (2 mL) containing a drop of conc. H2SO4 and the resulting mixture was stirred for 16 h. The reaction mixture was partitioned between EtOAc (10 mL) and saturated NaCl (5 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 80:20, gave the title compound. MS: m/z=218 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=[O:16])=O)(C)(C)C.[ClH:21].O1CCOCC1>COC1CCCC1>[ClH:21].[CH3:20][O:19][C@@H:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C@@H:14]([CH3:18])[C:15]([OH:17])=[O:16]
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: COC1CCCC1
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)O
Reaction time: 3 h
Yield: 31 %

Procedure:
To a mixture of #11 (4.09 g, 14.2 mmol, 1 eq.) in cyclopentyl methyl ether (10 mL, 0.14 M) was added a 4 N solution of hydrogen chloride in dioxane (37 mL, 100 mmol, 7 eq.). After three hours, the reaction mixture was concentrated in vacuo and azeotroped three times with heptane to give #103 (1000 mg, 31%) as a gum, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.92-10.06 (br s, 1H), 8.66-8.80 (br s, 1H), 3.89 (dd, J=5.2, 4.9 Hz, 1H), 3.43-3.53 (m, 1H), 3.39 (s, 3H), 3.06-3.17 (m, 2H), 2.66 (qd, J=7.1, 4.6 Hz, 1H), 1.71-2.03 (m, 4H), 1.11 (d, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]([P:8](=[O:11])([OH:10])[OH:9])=O.[H][H]>>[CH2:2]([NH:1][CH2:6][P:8]([OH:11])([OH:10])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: O=CP(=O)(O)O
Reactant: NCC(=O)O
Product: O=C(O)CNCP(=O)(O)O
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
Reaction of glycine and formylphosphonic acid was carried out in the manner described in Example 2 except that the amount of glycine used was increased slightly (1.9 g; 0.025 mole), a smaller amount of catalyst was supplied (0.1 g), and the pH was adjusted to 8.0. The system was maintained at the reaction temperature and pressure for 20 hours although hydrogen uptake ceased after 0.5 hour. The analysis indicated a 93.9% yield of glyphosate salt.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C([C:13](CC)([C:18]([O-:20])=[O:19])C(OBr)=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:29](C(C)=O)[CH3:30]>>[CH2:29]([O:20][C:18]([C:13]1[O:10][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=1)=[O:19])[CH3:30]
Reactant: CCC(CC)(C(=O)[O-])C(=O)OBr
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(Br)ccc2o1
Reaction time: 72 h
Yield: 78 %

Procedure:
A solution of 5-bromo-salicylaldehyde (5.0 g, 25 mmol) and bromo diethylmalonate (8.9 g, 37 mmol) in methyl ethyl ketone (50 mL) is treated with potassium carbonate (6.8 g, 50 mmol) and heated to reflux. The reaction is stirred over 3 days at reflux. The reaction is then concentrated to a crude solid that is purified by silica gel column chromatography (9:1 hexane/EtOAc) to afford 5.2 g (78%) of the desired product. 1H NMR (CDCl3) 7.81 (d, 1H), 7.26-7.55 (m, 3H), 4.44 (q, 2H), 1.42 (t, 3H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:45])[CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH2:35][CH2:36][C:37](=[O:44])[NH:38]2>>[OH:45][C@H:30]([CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH2:35][CH2:36][C:37](=[O:44])[NH:38]2)[CH2:29][NH:28][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.75-1.90 (m, 2H), 2.05 (s, 3H), 2.39 (t, J=7.5 Hz, 2H), 2.50-2.80 (m, 5H), 2.83 (t, J=7.5 Hz, 2H), 3.40-3.55 (m, 2H), 3.70-3.85 (m, 3H), 6.44 (d, J=8.7 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 6.76 (d, J=9.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 7.58 (d, J=9.0 Hz, 2H), 7.67 (d, J=9.0 Hz, 2H), 8.72 (s, 1H), 10.27 (s, 1H); MS (ES) m/z: 623.9 (MH+); HRMS Calcd. for C31H38N5O7S(MH+): 624.2492. Found: 624.2469.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl(O)(=O)=O.[CH2:12](O)[CH3:13]>>[CH2:12]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:7][C:1]1[CH:6]=[CH:5][C:4]([CH:12]=[CH2:13])=[CH:3][CH:2]=1
Reactant: CCO
Reactant: Cc1ccccc1
Agent: [O-][Cl+2]([O-])O
Product: C=Cc1ccc(C)cc1
Product: C=Cc1ccccc1

Procedure:
5 ml (50 μmol of Ti) of toluene solution in which the metallocene is dissolved were added while vigorously agitating. After agitating for 1 hour, 10 wt % of chloric acid-ethanol solution was added to terminate a reaction, the reactant was filtered, washed with ethanol and dried in a vacuum oven of 50° C. overnight to obtain a final styrene/p-methylstyrene copolymer.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11]OS(C)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C)C=O>[N:21]([CH2:11][CH2:10][C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)CCOS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CCN=[N+]=[N-])CCO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Yield: 59.4 %

Procedure:
Step B To the solution of methanesulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl ester (1.48 g, 4.96 mmol) in anhydrous dimethylformamide (10 mL) was added NaN3 (1.6 g, 25 mmol). The reaction mixture was heated at 60° C. for 18 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4 to give (5-azido-3,3-dimethyl-pentyloxy)-tert-butyl-dimethyl-silane as a yellow oil (0.8 g, 67%).
Reaction SMILES: C(C[N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15]C=2C(C2C=CC=CC=2)=N[CH:7]([NH:22]C(OCC2C=CC=CC=2)=O)[C:6]1=[O:33])(O)=O.C[N:35]1CCOCC1.C(OC(Cl)=O)C(C)C.CO[C:51](=O)[C@H:52]([C@H:54](CC)[CH3:55])N>O1CCCC1>[NH2:22][C@H:7]([C:6]([N:5]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=[N:35]1)=[O:33])[C@H:52]([CH2:54][CH3:55])[CH3:51]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: CN1CCOCC1
Reactant: O=C(O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)N1C=CC=CC=N1
Reaction time: 0.08 h
Yield: 274.6 %

Procedure:
To the benzodiazepin-2-one 29 (0.55 g, 1.23 mmol), in tetrahydrofuran (4 mL) at -20° C. under argon, was added NMM (0.14 mL, 1.23 mmol) followed by isobutylchloroformate (9.16 mL, 1.23 mmol). The mixture was stirred for 5 minutes, and then 0.14 mL (1.23 mmol) of NMM was added, followed by isoleucine methyl ester (0.22 g, 1.23 mmol) in tetrahydrafuran. This solution was stirred for 1 hour at -20° C., then 2 hours at room temperature. Tetrahydrafuran was removed in vacuum and the resulting solid was dissolved in ethylacetate, and the salts filtered off. The ethyl acetate extract was washed with 5% citric acid, 5% sodium bicarbonate solution, water, brine and dried over MgSO4. Solvent evaporated to give 0.70 g of the crude 2-isoleucyl diazepine 30. This was chromatographed on silica gel column using 40% ethyl acetate/60% hexane to give 0.59 g of pure 30 (92% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[C:21]([NH:25][CH2:26][C:27]([NH2:29])=[O:28])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:21]([N:25]([CH2:26][C:27](=[O:28])[NH2:29])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NCC(N)=O
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N(CC(N)=O)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-(tert-butylamino)acetamide (207925-15-3) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=397.5 [MH+].
Reaction SMILES: [C:1]([C:3]1[N:13]=[CH:12][C:6]2[N:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)#[N:2].C([Sn]([N:27]=[N+:28]=[N-:29])(CCCC)CCCC)CCC>COCCOCCOC>[NH:27]1[C:1]([C:3]2[N:13]=[CH:12][C:6]3[N:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]=3[CH:4]=2)=[N:2][N:29]=[N:28]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1cc2c(=O)[nH]cnc2cn1
Solvent: COCCOCCOC
Product: O=c1[nH]cnc2cnc(-c3nnn[nH]3)cc12
Yield: 440.9 %

Procedure:
6-Cyano-pyrido[3,4-d]pyrimidin-4-one (0.3 g) in diglyme (2 ml) was treated with tributyl tin azide (0.49 g) at reflux under N2 for 15 hours. The cooled mixture was partitioned between ethyl acetate and water and the aqueous phase extracted further with ethyl acetate. The aqueous phase was concentrated in vacuo, the residue taken up in methanol and inorganics removed by filtration. Subsequent concentration gave the title compound (1.4 g) as a beige solid; δH [2H6]DMSO 8.96 (1H,s), 8.50 (1H,s), 8.27 (1H,s); m/z (M+1+) 216.